{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRan is a highly conserved small GTPase that establishes a RanGTP‐to–RanGDP gradient essential for directional nucleocytoplasmic transport. This gradient, generated by the chromatin‐bound guanine nucleotide exchange factor RCC1, orchestrates the release of cargoes from importin complexes and controls nuclear export through receptors such as CRM1. In turn, these mechanisms underlie critical processes such as nuclear envelope reassembly, proper chromosomal segregation during mitosis, and the assembly and stabilization of the microtubule spindle—functions supported by regulation of spindle assembly factors (e.g. TPX2 and Kid) and by direct modulation of nucleoporin interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical roles in nuclear transport and spindle assembly, Ran participates in diverse signaling pathways that impact cell fate and disease. Ran‐dependent nuclear import is critical for the proper localization and function of key regulatory proteins such as STAT3, PU.1, and the tumor suppressor PTEN, while disruption of Ran’s gradient and transport capacity—often triggered by cellular stress, altered ATP levels, or pathogenic proteins like progerin—can lead to aberrant gene expression and apoptosis. In cancer, elevated Ran protein expression or its mis‐regulation is associated with aggressive phenotypes in ovarian, renal, and neuroblastoma tumors, and Ran’s interactions with oncogenic factors (for example, through modulation of RhoA stability at the plasma membrane) further implicate it in tumor cell invasion and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies have uncovered unconventional functions of Ran. Under conditions of repetitive nucleotide expansion, non‐AUG (RAN) translation produces toxic peptides implicated in neurodegenerative disorders such as fragile X–associated tremor/ataxia syndrome and myotonic dystrophy type 2. Moreover, Ran influences microRNA biogenesis and modulates the intracellular distribution of proteins involved in ciliary assembly, nuclear size regulation, and cytoskeletal organization. Beyond its role as a molecular switch in transport, Ran interacts with accessory factors such as RanBP, NTF2, and Epac1 to coordinate cellular responses during stress and development, thereby integrating signaling cascades that regulate cell proliferation, differentiation, and survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael J Seewald, Astrid Kraemer, Marian Farkasovsky, et al. 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